What is LEOPARD (Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonic stenosis, Abnormalities of the genitals, Retardation of growth, and sensorineural Deafness) syndrome?

From the Guidelines

LEOPARD syndrome is a rare genetic disorder characterized by multiple abnormalities affecting various body systems, including lentigines, electrocardiographic conduction defects, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, and deafness, caused by mutations in the PTPN11, RAF1, or BRAF genes, as noted in a recent study 1.

Key Features of LEOPARD Syndrome

• Lentigines: multiple dark spots on the skin, appearing predominantly around the ages 4 to 5 years as hypertrophic, black-brown macules occurring on the face 1
• Electrocardiographic conduction defects: requiring regular monitoring with echocardiograms and ECGs
• Ocular hypertelorism: widely spaced eyes
• Pulmonary stenosis: may require surgical correction if severe
• Abnormalities of genitalia: varying degrees of severity
• Retardation of growth: may be addressed with growth hormone therapy
• Deafness: may be managed with hearing aids

Management and Treatment

• A multidisciplinary approach is essential for managing LEOPARD syndrome, focusing on each patient's specific manifestations 1
• Cardiac issues, particularly hypertrophic cardiomyopathy, are the most serious concerns and require regular monitoring with echocardiograms and ECGs
• Treatment may include beta-blockers like metoprolol or propranolol for cardiac symptoms
• Surgical correction of pulmonary stenosis if severe
• Hearing aids for those with hearing loss
• Growth hormone therapy might be considered for significant growth delays
• Regular skin examinations are important as patients have an increased risk of skin cancers
• Genetic counseling is essential for affected individuals and their families to understand inheritance patterns and reproductive options
• Early intervention services can help address developmental delays that may be present

Importance of Recent Guidelines

• The most recent study on LEOPARD syndrome, published in 2024, provides updated information on the condition's characteristics and management 1
• This study highlights the importance of a multidisciplinary approach in managing LEOPARD syndrome, focusing on each patient's specific manifestations
• The study also notes the increased risk of skin cancers in patients with LEOPARD syndrome, emphasizing the need for regular skin examinations.

From the Research

Definition and Characteristics of LEOPARD Syndrome

• LEOPARD syndrome is a rare multiple congenital anomalies condition, mainly characterized by skin, facial, and cardiac anomalies 2.
• The acronym LEOPARD stands for the major features of this disorder, including multiple Lentigines, ECG conduction abnormalities, Ocular hypertelorism, Pulmonic stenosis, Abnormal genitalia, Retardation of growth, and sensorineural Deafness 2, 3, 4.
• Facial dysmorphism includes ocular hypertelorism, palpebral ptosis, and low-set ears, and stature is usually below the 25th centile 2.
• Cardiac defects, in particular hypertrophic cardiomyopathy, and ECG anomalies are common 2, 5, 4.

Clinical Diagnosis and Molecular Basis

• The clinical diagnosis of LEOPARD syndrome is generally difficult in the first months of life because the distinctive lentigines are generally not present at birth and develop during childhood 3.
• Molecular studies have shown that LEOPARD syndrome is caused by different missense mutations in the PTPN11 gene, which encodes the protein tyrosine phosphatase SHP-2 2, 3, 4, 6.
• Mutation analysis can be carried out on blood, chorionic villi, and amniotic fluid samples, and a PTPN11 gene mutation is detected in about 85% of the cases 2.

Clinical Management and Prognosis

• Clinical management should address growth and motor development and congenital anomalies, in particular cardiac defects that should be monitored annually 2.
• Hypertrophic cardiomyopathy needs careful risk assessment and prophylaxis against sudden death in patients at risk 2, 5, 4.
• Hearing should be evaluated annually until adulthood, and with the only exception of ventricular hypertrophy, adults with LEOPARD syndrome do not require special medical care and long-term prognosis is favourable 2.

Differential Diagnosis

• LEOPARD syndrome should be suspected in patients with multiple lentigines, hypertrophic cardiomyopathy, and deafness, and mutation-based differential diagnosis is warranted in patients with borderline clinical manifestations 2, 3.
• LEOPARD syndrome is largely overlapping with Noonan syndrome, and during childhood, Neurofibromatosis type 1-Noonan syndrome 2, 3.